Adult Human Brain Research Articles

A Standardized Protocol for the Safe Retrieval of Infectious Postmortem Human Brain for Studying Whole-Brain Pathology.

We describe a safe and standardized perfusion protocol for studying brain pathology in high-risk autopsies using a custom-designed low-cost infection containment chamber and high-resolution histology. The output quality was studied using the histological data from the whole cerebellum and brain stem processed using a high-resolution cryohistology pipeline at 0.5 μm per pixel, in-plane resolution with serial sections at 20-μm thickness. To understand the pathophysiology of highly infectious diseases, it is necessary to have a safe and cost-effective method of performing high-risk autopsies and a standardized perfusion protocol for preparing high-quality tissues. Using the low-cost infection containment chamber, we detail the cranial autopsy protocol and ex situ perfusion-fixation of 4 highly infectious adult human brains. The digitized high-resolution histology images of the Nissl-stained series reveal that most of the sections were free of processing artifacts, such as fixation damage, freezing artifacts, and osmotic shock, at the macrocellular and microcellular level. The quality of our protocol was also tested with the highly sensitive immunohistochemistry staining for specific protein markers. Our protocol provides a safe and effective method in high-risk autopsies that allows for the evaluation of pathogen-host interaction, the underlying pathophysiology, and the extent of the infection across the whole brain at microscopic resolutions.

Unfolding the direct connectivity of the occipital cortex with the hypothalamic, septal and BNST nuclei of the human brain

The hypothalamus plays essential roles in the human brain by regulating feeding, fear, aggression, reproductive behaviors, and autonomic activities. The septal nuclei and the bed nucleus of stria terminalis (BNST) are also known to be involved in control of autonomic, motivational, learning, emotional and associative processes in the human brain. Multiple animal dissection studies have revealed direct connectivity between central limbic gray matter nuclei and occipital cortex, particularly from the hypothalamic, septal and BNST nuclei. However, the detailed anatomy of this connectivity in the human brain has yet to be determined. The primary objective of this study was to explore the utility of high spatial and high angular resolution diffusion weighted tractography techniques for mapping the connectivity pathways between the occipital cortex and central limbic gray matter nuclei in the human brain. We studied 30 healthy adult human brains, delineated, and reconstructed the trajectory of the occipito-hypothalamic/septal/BNST for the first time in the human brain.

Parallel processing relies on a distributed, low-dimensional cortico-cerebellar architecture.

A characteristic feature of human cognition is our ability to 'multi-task'-performing two or more tasks in parallel-particularly when one task is well learned. How the brain supports this capacity remains poorly understood. Most past studies have focussed on identifying the areas of the brain-typically the dorsolateral prefrontal cortex-that are required to navigate information-processing bottlenecks. In contrast, we take a systems neuroscience approach to test the hypothesis that the capacity to conduct effective parallel processing relies on a distributed architecture that interconnects the cerebral cortex with the cerebellum. The latter structure contains over half of the neurons in the adult human brain and is well suited to support the fast, effective, dynamic sequences required to perform tasks relatively automatically. By delegating stereotyped within-task computations to the cerebellum, the cerebral cortex can be freed up to focus on the more challenging aspects of performing the tasks in parallel. To test this hypothesis, we analysed task-based fMRI data from 50 participants who performed a task in which they either balanced an avatar on a screen (balance), performed serial-7 subtractions (calculation) or performed both in parallel (dual task). Using a set of approaches that include dimensionality reduction, structure-function coupling, and time-varying functional connectivity, we provide robust evidence in support of our hypothesis. We conclude that distributed interactions between the cerebral cortex and cerebellum are crucially involved in parallel processing in the human brain.

Analysis of free-fall bullet injury potential in the cranium via finite elements method

The aim of this study is to analyze the injury potential of the free-falling bullet in the cranium, which is known as a tired bullet in the public, with the finite element method (FEM) In the study, as penetrant 9 × 19 mm FMJ bullets with vertical falling angle, adult human skull and brain tissue were discussed. The results of the analysis with the Finite element method, which is similar to the cases reported before, revealed that free-falling bullets as a result of shooting into the air can cause fatal injuries.

Morphological study of neuropeptide Y expression in human and mouse anterior insular cortex: Overexpression in the insular cortex and nucleus accumbens in obese mice on a long-term obesogenic diet

BackgroundThe anterior lobe of the insular cortex (aINS) is a cortical region that has reciprocal connections with limbic centers such as the anterior cingulate cortex, prefrontal cortex, amygdala and nucleus accumbens (NAc). In fact, the aINS has been involved in the integration of autonomic information for emotional and motivational functions. The compulsive consumption of drugs or high-fat foods induces alterations at both behavioural and brain levels. Brain reward circuits are altered in response to continued intake, in particular the dopaminergic projections from the ventral tegmental area (VTA) to the NAc. The aINS has multiple connections with the components of this system. In recent years, efforts have been made to better understand the fundamental role of the aINS in addiction, making it one of the key centres of interest for research into new treatments for addiction. ObjectivesThe present work focuses on studying 1.- whether the human aINS expresses orexigenic peptides such as neuropeptide Y (NPY), a peptide known to induce hyperphagia, and which has been implicated in the onset and development of obesity, 2.- the long-term effect of an obesogenic diet on NPY expression in the aINS and NAc of C57BL/6 mice. MethodsA total of 17 female C57BL/6 J mice were used in this study. Female mice were fed ad libitum with water and, either a standard diet (SD) or a high-fat diet (HFD) to induce obesity. There were seven female mice on the SD and ten on the HFD. The duration of the experiment was 180 days. We also studied 3 human adult brains (1 male and 2 females, mean age 55.7 ± 5.2 years). The morphological study was performed using immunohistochemistry and double immunofluorescence techniques to study the neurochemical profile of NPY neurons of the aINS and NAc of humans and mice. ResultsOur morphological analysis demonstrates for the first time the basal expression of NPY in different layers of the human cortex (II, III, IV, V/VI), in a pattern similar to previous studies in other species. Furthermore, we observed an increase in the number of NPY-positive cells and their intracytoplasmic signal in the aINS and NAc of the obese mice subjected to a long-term obesogenic diet. ConclusionsTo our knowledge, this is the first study to show the distribution and expression of NPY in the human INS and how its expression is altered after prolonged treatment with an obesogenic diet in obese mice. Our findings may contribute to the understanding of the pathophysiological mechanisms underlying obesity in regions related to the reward system and associated with uncontrolled intake of high-fat foods, thus facilitating the identification of novel therapeutic targets.

Human Brain Organoids: Why There Can Be Moral Concerns If They Grow Up in the Lab and Are Transplanted or Destroyed.

Human brain organoids (HBOs) are three-dimensional biological entities grown in the laboratory in order to recapitulate the structure and functions of the adult human brain. They can be taken to be novel living entities for their specific features and uses. As a contribution to the ongoing discussion on the use of HBOs, the authors identify three sets of reasons for moral concern. The first set of reasons regards the potential emergence of sentience/consciousness in HBOs that would endow them with a moral status whose perimeter should be established. The second set of moral concerns has to do with an analogy with artificial womb technology. The technical realization of processes that are typically connected to the physiology of the human body can create a manipulatory and instrumental attitude that can undermine the protection of what is human. The third set concerns the new frontiers of biocomputing and the creation of chimeras. As far as the new frontier of organoid intelligence is concerned, it is the close relationship of humans with new interfaces having biological components capable of mimicking memory and cognition that raises ethical issues. As far as chimeras are concerned, it is the humanization of nonhuman animals that is worthy of close moral scrutiny. A detailed description of these ethical issues is provided to contribute to the construction of a regulative framework that can guide decisions when considering research in the field of HBOs.

The Role of Tau Proteoforms in Health and Disease.

Tau is a microtubule-associated binding protein in the nervous system that is known for its role in stabilizing microtubules throughout the nerve cell. It accumulates as β-sheet-rich aggregates and neurofibrillary tangles, leading to an array of different pathologies. Six splice variants of this protein, generated from the microtubule-associated protein tau (MAPT) gene, are expressed in the brain. Amongst these variants,0N3R, is prominent during fetal development, while the rest, 0N4R, 1N3R, 1N4R, 2N3R, and 2N4R, are expressed in postnatal stages. Tau isoforms play their role separately or in combination with others to contribute to one or multiple neurodegenerative disorders and clinical syndromes. For instance, in Alzheimer's disease and a subset of frontotemporal lobar degeneration (FTLD)-MAPT (i.e., R406W and V337M), both 3R and 4R isoforms are involved; therefore, they are called 3R/4R mix tauopathies. On the other hand, 4R isoforms are aggregated in progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and a majority of FTLD-MAPT and these diseases are called 4R tauopathies. Similarly, Pick's disease has an association with 3R tau isoforms and is thereby referred to as 3R tauopathy. Unlike 3R isoforms, the 4R variants have a faster rate of aggregation that accelerates the associated neurodegenerative mechanisms. Moreover, post-translational modifications of each isoform occur at a different rate and dictate their physiological and pathological attributes. The smallest tau isoform (0N3R) is highly phosphorylated in the fetal brain but does not lead to the generation of aggregates. On the other hand, proteoforms in the adult human brain undergo aggregation upon their phosphorylation and glycation. Expanding on this knowledge, this article aims to review the physiological and pathological roles of tau isoforms and their underlying mechanisms that result in neurological deficits. Physiological and pathological relevance of microtubule-associated protein tau (MAPT): Tau exists as six splice variants in the brain, each differing with respect to expression, post-translational modifications (PTMs), and aggregation kinetics. Physiologically, they are involved in the stabilization of microtubules that form the molecular highways for axonal transport. However, an imbalance in their expression and the associated PTMs leads to a disruption in their physiological function through the formation of neurofibrillary tangles that accumulate in various regions of the brain and contribute to several types of tauopathies.

Tau deficiency protects human neurons from Abeta‐induced reduction of network activity

AbstractBackgroundOne hallmark of many neurodegenerative diseases, such as Alzheimer’s disease (AD), is the formation of neurofibrillary tangles by hyperphosphorylated Tau in the brain, resulting in neuronal death and cognitive decline. In the adult human brain, six Tau‐isoforms are expressed, originating from alternative splicing of exons 2, 3, and 10 of the MAPT gene. The isoforms differ in the number of N‐terminal inserts (0, 1, or 2N) and the C‐terminal repeat number (3 or 4R). Recent results from murine neurons highlight that the six human‐specific isoforms are differentially localized within neurons and influence microtubule dynamics in an isoform‐specific manner. In this study, we generated a human neuronal model system to further characterize the human‐specific Tau‐isoforms under basic and pathological conditions.MethodWe successfully generated three Tau KO hiPSC cell lines derived from Ngn2‐WTC11 cells using CRISPR/Cas9 and characterized the generated cell lines using genetic, biochemical and microscopy‐based methods.ResultNo difference between Tau KO and WT hiPSCs was observed in the capability of neuronal differentiation or neuronal morphology. Interestingly, Tau KO neurons were shown to be resistant to an Abeta‐induced reduction of network activity. Initial results from re‐expressed Tau‐isoforms in these neurons support the differential localization of the isoforms observed previously. Further experiments will investigate the isoform‐specific role of Tau regarding microtubule dynamics, axonal branching, and synapse formation under basal and pathological conditions.ConclusionTau KO hiPSCs are a versatile tool to study basic as well as pathological functions of Tau. Expected results will provide a major understanding of Tau function and help identifying potential therapeutic targets for the treatment of AD and related neurodegenerative diseases.

Thyroid Hormone Transporters MCT8 and OATP1C1 Are Expressed in Projection Neurons and Interneurons of Basal Ganglia and Motor Thalamus in the Adult Human and Macaque Brains.

Monocarboxylate transporter 8 (MCT8) and organic anion-transporting polypeptide 1C1 (OATP1C1) are thyroid hormone (TH) transmembrane transporters relevant for the availability of TH in neural cells, crucial for their proper development and function. Mutations in MCT8 or OATP1C1 result in severe disorders with dramatic movement disability related to alterations in basal ganglia motor circuits. Mapping the expression of MCT8/OATP1C1 in those circuits is necessary to explain their involvement in motor control. We studied the distribution of both transporters in the neuronal subpopulations that configure the direct and indirect basal ganglia motor circuits using immunohistochemistry and double/multiple labeling immunofluorescence for TH transporters and neuronal biomarkers. We found their expression in the medium-sized spiny neurons of the striatum (the receptor neurons of the corticostriatal pathway) and in various types of its local microcircuitry interneurons, including the cholinergic. We also demonstrate the presence of both transporters in projection neurons of intrinsic and output nuclei of the basal ganglia, motor thalamus and nucleus basalis of Meynert, suggesting an important role of MCT8/OATP1C1 for modulating the motor system. Our findings suggest that a lack of function of these transporters in the basal ganglia circuits would significantly impact motor system modulation, leading to clinically severe movement impairment.

Analysis of the microglia transcriptome across the human lifespan using single cell RNA sequencing

BackgroundMicroglia are tissue resident macrophages with a wide range of critically important functions in central nervous system development and homeostasis.MethodIn this study, we aimed to characterize the transcriptional landscape of ex vivo human microglia across different developmental ages using cells derived from pre-natal, pediatric, adolescent, and adult brain samples. We further confirmed our transcriptional observations using ELISA and RNAscope.ResultsWe showed that pre-natal microglia have a distinct transcriptional and regulatory signature relative to their post-natal counterparts that includes an upregulation of phagocytic pathways. We confirmed upregulation of CD36, a positive regulator of phagocytosis, in pre-natal samples compared to adult samples in situ. Moreover, we showed adult microglia have more pro-inflammatory signature compared to microglia from other developmental ages. We indicated that adult microglia are more immune responsive by secreting increased levels of pro-inflammatory cytokines in response to LPS treatment compared to the pre-natal microglia. We further validated in situ up-regulation of IL18 and CXCR4 in human adult brain section compared to the pre-natal brain section. Finally, trajectory analysis indicated that the transcriptional signatures adopted by microglia throughout development are in response to a changing brain microenvironment and do not reflect predetermined developmental states.ConclusionIn all, this study provides unique insight into the development of human microglia and a useful reference for understanding microglial contribution to developmental and age-related human disease.

Multi-scale systems genomics analysis predicts pathways, cell types, and drug targets involved in normative variation in peri-adolescent human cognition.

An open challenge in human genetics is to better understand the systems-level impact of genotype variation on developmental cognition. To characterize the genetic underpinnings of peri-adolescent cognition, we performed genotype-phenotype and systems analysis for binarized accuracy in nine cognitive tasks from the Philadelphia Neurodevelopmental Cohort (~2,200 individuals of European continental ancestry aged 8-21years). We report a region of genome-wide significance within the 3' end of the Fibulin-1 gene (P= 4.6 × 10-8), associated with accuracy in nonverbal reasoning, a heritable form of complex reasoning ability. Diffusion tensor imaging data from a subset of these participants identified a significant association of white matter fractional anisotropy with FBLN1 genotypes (P< 0.025); poor performers show an increase in the C and A allele for rs77601382 and rs5765534, respectively, which is associated with increased fractional anisotropy. Integration of published human brain-specific 'omic maps, including single-cell transcriptomes of the developing human brain, shows that FBLN1 demonstrates greatest expression in the fetal brain, as a marker of intermediate progenitor cells, demonstrates negligible expression in the adolescent and adult human brain, and demonstrates increased expression in the brain in schizophrenia. Collectively these findings warrant further study of this gene and genetic locus in cognition, neurodevelopment, and disease. Separately, genotype-pathway analysis identified an enrichment of variants associated with working memory accuracy in pathways related to development and to autonomic nervous system dysfunction. Top-ranking pathway genes include those genetically associated with diseases with working memory deficits, such as schizophrenia and Parkinson's disease. This work advances the "molecules-to-behavior" view of cognition and provides a framework for using systems-level organization of data for other biomedical domains.

Nucleolin promotes angiogenesis and endothelial metabolism along the oncofetal axis in the human brain vasculature.

Glioblastomas are among the deadliest human cancers and are highly vascularized. Angiogenesis is dynamic during brain development, almost quiescent in the adult brain but reactivated in vascular-dependent CNS pathologies, including brain tumors. The oncofetal axis describes the reactivation of fetal programs in tumors, but its relevance in endothelial and perivascular cells of the human brain vasculature in glial brain tumors is unexplored. Nucleolin is a regulator of cell proliferation and angiogenesis, but its roles in the brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit in human fetal brains, adult brains, and human gliomas in vivo as well as its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression correlated with glioma malignancy in vivo. In culture, siRNA-mediated Nucleolin knockdown reduced human brain endothelial cell (HCMEC) and HUVEC sprouting angiogenesis, proliferation, filopodia extension, and glucose metabolism. Furthermore, inhibition of Nucleolin with the aptamer AS1411 decreased brain endothelial cell proliferation in vitro. Mechanistically, Nucleolin knockdown in HCMECs and HUVECs uncovered regulation of angiogenesis involving VEGFR2 and of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that promotes sprouting angiogenesis and endothelial metabolism, characterizing Nucleolin as an oncofetal protein. Our findings have potential implications in the therapeutic targeting of glioma.

Cortical Layer Markers Expression and Increased Synaptic Density in Interstitial Neurons of the White Matter from Drug-Resistant Epilepsy Patients.

The interstitial neurons in the white matter of the human and non-human primate cortex share a similar developmental origin with subplate neurons and deep-layer cortical neurons. A subset of interstitial neurons expresses the molecular markers of subplate neurons, but whether interstitial neurons express cortical layer markers in the adult human brain remains unexplored. Here we report the expression of cortical layer markers in interstitial neurons in the white matter of the adult human brain, supporting the hypothesis that interstitial neurons could be derived from cortical progenitor cells. Furthermore, we found increased non-phosphorylated neurofilament protein (NPNFP) expression in interstitial neurons in the white matter of drug-resistant epilepsy patients. We also identified the expression of glutamatergic and g-aminobutyric acid (GABAergic) synaptic puncta that were distributed in the perikarya and dendrites of interstitial neurons. The density of glutamatergic and GABAergic synaptic puncta was increased in interstitial neurons in the white matter of drug-resistant epilepsy patients compared with control brain tissues with no history of epilepsy. Together, our results provide important insights of the molecular identity of interstitial neurons in the adult human white matter. Increased synaptic density of interstitial neurons could result in an imbalanced synaptic network in the white matter and participate as part of the epileptic network in drug-resistant epilepsy.

385 A Cell Resolution Atlas of the Human Cerebrovasculature Reveals Angiogenic and Inflammatory Cell Programs in Arteriovenous Malformations

INTRODUCTION: Coordinated communications between multiple cell types is responsible for cerebrovascular structure and function. Cellular dysfunction results in cerebrovascular diseases, a leading cause of death and disability. However, we lack a complete census of human cerebrovascular cells necessary to advance understanding of disease mechanisms and therapeutic strategies. METHODS: To provide a human cerebrovascular cell atlas, we used single-cell RNA sequencing (scRNAseq) to molecularly profile dissociated vascular cells isolated from the adult human brain and AVMs. Joint comparative analyses profiled patterns of aberrant gene expression in AVMs and resolved cell states enriched in AVMs that bled. Results were validated with fluorescent in situ hybridization, immunostaining, and in vitro functional assays RESULTS: By performing scRNAseq on 181,388 single-cells, we identified &gt; 40 molecularly-defined vascular or neighboring cell states from the human cerebrovasculature and AVMs. We identified endothelial molecular signatures underlying arteriovenous phenotypic changes known as “zonations.” Our study uncovered an expanded diversity of perivascular cells unique to humans. In AVMs, there was a loss of normal arteriovenous molecular patterning characterized by the emergence of an endothelial cell state with heightened angiogenic potential and immune cell cross-talk within the AVM nidus. We characterized the cellular ontology of cerebrovascular-derived immune cell response and identified infiltration of distinct immune cell states, such as GPNMB+ monocytes, which deplete stabilizing smooth muscle cells in AVMs that bled. CONCLUSIONS: Our single-cell atlas highlighted the heterogeneity underlying cell function and interaction in the human cerebrovasculature and defined molecular and cellular perturbations in AVMs, a leading cause of stroke in young people. The identified interplay between vascular and immune cells will aid development of therapeutics targeting angiogenic and inflammatory programs in vascular malformations.

The Venous Circle of Trolard: An Anatomical Study with Application to Approaches to the Basal Brain

The arterial circle of Willis is a well-known and interconnecting set of blood vessels at the base of the brain. However, its lesser-known venous counterpart, the circle of Trolard, has had almost no attention in the extant medical literature. Twenty-four adult human brains underwent dissection of the circle of Trolard. When identified, its component vessels and relationships with adjacent structures were confirmed and documented with photography and measured using microcalipers. A complete circle of Trolard was identified on 42% of specimens. Most (64%) incomplete circles were incomplete anteriorly with no anterior communicating vein. The anterior communicating veins joined the anterior cerebral veins superior to the optic chiasm and continued posteriorly. The anterior communicating veins had a mean diameter of 0.45 mm. The length of these veins ranged from 0.8 mm to 1.45 mm. Thirty-six percent of circles were incomplete posteriorly with lack of a posterior communicating vein. The posterior communicating veins were always larger and longer than the anterior cerebral veins. The posterior communicating veins had a mean diameter of 0.8 mm. The length of these veins ranged from 2.8 to 3.9 cm. In general, the circles of Trolard were more or less symmetrical. However, in 2 specimens, asymmetry existed. A better understanding of the venous circle of Trolard might decrease iatrogenic injury during approaches to the base of the brain and improve diagnoses based on imaging of the skull base. To our knowledge, this is the first anatomical study dedicated to the circle of Trolard.

Spatial epigenome–transcriptome co-profiling of mammalian tissues

Emerging spatial technologies, including spatial transcriptomics and spatial epigenomics, are becoming powerful tools for profiling of cellular states in the tissue context1–5. However, current methods capture only one layer of omics information at a time, precluding the possibility of examining the mechanistic relationship across the central dogma of molecular biology. Here, we present two technologies for spatially resolved, genome-wide, joint profiling of the epigenome and transcriptome by cosequencing chromatin accessibility and gene expression, or histone modifications (H3K27me3, H3K27ac or H3K4me3) and gene expression on the same tissue section at near-single-cell resolution. These were applied to embryonic and juvenile mouse brain, as well as adult human brain, to map how epigenetic mechanisms control transcriptional phenotype and cell dynamics in tissue. Although highly concordant tissue features were identified by either spatial epigenome or spatial transcriptome we also observed distinct patterns, suggesting their differential roles in defining cell states. Linking epigenome to transcriptome pixel by pixel allows the uncovering of new insights in spatial epigenetic priming, differentiation and gene regulation within the tissue architecture. These technologies are of great interest in life science and biomedical research.

Microstructural and neurochemical plasticity mechanisms interact to enhance human perceptual decision-making.

Experience and training are known to boost our skills and mold the brain's organization and function. Yet, structural plasticity and functional neurotransmission are typically studied at different scales (large-scale networks, local circuits), limiting our understanding of the adaptive interactions that support learning of complex cognitive skills in the adult brain. Here, we employ multimodal brain imaging to investigate the link between microstructural (myelination) and neurochemical (GABAergic) plasticity for decision-making. We test (in males, due to potential confounding menstrual cycle effects on GABA measurements in females) for changes in MRI-measured myelin, GABA, and functional connectivity before versus after training on a perceptual decision task that involves identifying targets in clutter. We demonstrate that training alters subcortical (pulvinar, hippocampus) myelination and its functional connectivity to visual cortex and relates to decreased visual cortex GABAergic inhibition. Modeling interactions between MRI measures of myelin, GABA, and functional connectivity indicates that pulvinar myelin plasticity interacts-through thalamocortical connectivity-with GABAergic inhibition in visual cortex to support learning. Our findings propose a dynamic interplay of adaptive microstructural and neurochemical plasticity in subcortico-cortical circuits that supports learning for optimized decision-making in the adult human brain.

A systematic review of fMRI studies of healthy adult human brain activation on learning and memory patterns for numerals

This systematic review examines the empirical evidence from previous fMRI studies on brain activation areas for learning and memory patterns for numerals to understand the question of the brain activation areas found from previous fMRI studies on learning and memory patterns for numerals. Relevant articles in the fields of psychology, neuroscience, paediatrics, and education were extracted from the PubMed database. Keyword searches included "learning", "memory", "brain", "digits", "numerals", and "fMRI". The database search was conducted from July 2022 to August 2022. The data collected was limited to English texts, and studies involving animal experiments were excluded. The remaining articles were screened based on the inclusion and exclusion criteria. Articles included in this review were selected from the database search between 1999 to 2022. Ten full-text articles were identified and evaluated. Examination of brain activation regions in learning and memory patterns for numerals revealed that 30% of studies (n=3) found activation in the hippocampus, inferior parietal lobe and parietal lobe. Subsequently, 20% of the studies (n=2) found activation in the anterior cingulate, caudate nucleus, cerebellum, frontal lobe, inferior frontal gyrus, inferior temporal gyrus, medial temporal lobe, occipital lobe, prefrontal cortex, striatum, and thalamus. The frontoparietal network is considered important for working memory, while the limbic areas are essential for learning and memory. Therefore, future studies should look more closely at the brain's functional and structural regions involved in learning and a more specific memory system.

Characterization of the Tau Interactome in Human Brain Reveals Isoform-Dependent Interaction with 14-3-3 Family Proteins.

Despite exhibiting tau phosphorylation similar to Alzheimer's disease (AD), the human fetal brain is remarkably resilient to tau aggregation and toxicity. To identify potential mechanisms for this resilience, we used co-immunoprecipitation (co-IP) with mass spectrometry to characterize the tau interactome in human fetal, adult, and Alzheimer's disease brains. We found significant differences between the tau interactome in fetal and AD brain tissue, with little difference between adult and AD, although these findings are limited by the low throughput and small sample size of these experiments. Differentially interacting proteins were enriched for 14-3-3 domains, and we found that the 14-3-3-β, η, and γ isoforms interacted with phosphorylated tau in Alzheimer's disease but not the fetal brain. Since long isoform (4R) tau is only seen in the adult brain and this is one of the major differences between fetal and AD tau, we tested the ability of our strongest hit (14-3-3-β) to interact with 3R and 4R tau using co-immunoprecipitation, mass photometry, and nuclear magnetic resonance (NMR). We found that 14-3-3-β interacts preferentially with phosphorylated 4R tau, forming a complex consisting of two 14-3-3-β molecules to one tau. By NMR, we mapped 14-3-3 binding regions on tau that span the second microtubule binding repeat, which is unique to 4R tau. Our findings suggest that there are isoform-driven differences between the phospho-tau interactome in fetal and Alzheimer's disease brain, including differences in interaction with the critical 14-3-3 family of protein chaperones, which may explain, in part, the resilience of fetal brain to tau toxicity.

Adult hippocampal neurogenesis in Alzheimer's disease: A roadmap to clinical relevance.

Adult hippocampal neurogenesis (AHN) drops sharply during early stages of Alzheimer's disease (AD), via unknown mechanisms, and correlates with cognitive status in AD patients. Understanding AHN regulation in AD could provide a framework for innovative pharmacological interventions. We here combine molecular, behavioral, and clinical data and critically discuss the multicellular complexity of the AHN niche in relation to AD pathophysiology. We further present a roadmap toward a better understanding of the role of AHN in AD by probing the promises and caveats of the latest technological advancements in the field and addressing the conceptual and methodological challenges ahead.